This invention relates to a pharmacological means of inducing the entire physiological course of labor at an accelerated rate, or of accelerating labor in process, in mammals, particularly farm animals.
Controlled parturition in cattle has been a subject of veterinary investigation for over a dozen years. Aside from possible clinical reasons for inducing labor before its spontaneous onset, in large dairy herds, such a regimen could have economic significance if births could be planned or occur at manageable rates for the available personnel during their normal working hours. So far, three categories of substance have been tested for this purpose: steroids such as dexamethasone of flumethasone, prostaglandins and oxytocin.
Steroids can induce parturition within 72 hours of i.m. injection of doses around 20 mg/cow. Part of the mechanism of action involves a relaxation of the uterine cervix. There are, however, two specific difficulties: (1) a 72 hour period still does not allow one to predict whether the calf will be born during a given working day so that the newly born can be put by hand to sucking colostrum soon after birth which is associated with less post-natal disease than in calves born at night or on weekends and left without such care; (2) objections can be raised to the use of large steroid doses in general since residues are left in milk and meat for long periods. Prostaglandins have a much shorter biochemical half-life than steroids and their onset of action is more rapid, but there is a danger of putting the uterus into tetany, which endangers both the cow and the fetus.
Oxytocin (OT) in moderate dosage produces regular contractions of the pregnant uterus, but for very short periods of time after single doses and in addition vasoconstricts the blood supply to the uterus. Attempts to prolong the effect by giving excessive doses can result in uterine tetany or tachyphylaxis, both of which, as with prostaglandins, endanger the lives of mother and fetus. In human use, OT is given in continuous infusion at 1 ml/min of a solution of 20 IU/l.--which represents a rate of about 40 ng or pmol/min--in 5% glucose, but constant monitoring of uterine contractions and fetal heartbeat are required to prevent tetany and fetal damage. Reports of use in bovine obstetrics vary from a failure to induce labor with i.v. or i.m. injection of 100 IU (=about 0.2 mg.) to successful induction with i.v. infusion of only 4--5 IU over 1 hour (but in only 3 animals). A long-acting analog of OT could, thus, obviate such difficulties with tetany and tachyphylaxis, and in particular the practical impossibility of routine setting up of long term infusions in large animals, by accomplishing the desired effect with one or, at most, two, separate i.v. injections.
Thus, the natural hormone has a number of disadvantages: (a) the actions following separate injections are very short-lived, so that to induce labor in a cow it must be injected at 30-min. intervals, which is difficult and often impossible for the veterinary physician on practical grounds; (b) it can be used usually only after considerable dilation of the cervix has occurred; otherwise, particularly if larger doses are used in order to get sufficient duration of action, there is danger of uterine tetany which can endanger the life of both fetus and mother; and (c) natural oxytocin also produces vasoconstriction in the uterus, which is disadvantageous to the fetus (Goodman, L. S. & Gilman, A., Chapter on "Ocytocics" in "The Pharmacological Basis of Therapeutics". Macmillan Co., New York, 1965).
It would be of advantage to have an oxytocic drug which would, after one or, at most, two single injections, result in an oxytocic response starting within minutes of administration and lasting for several hours--of sufficient duration to cover the course of accelerated labor. Analogs of oxytocin have been described with a prolonged oxytocic activity such as 1-deamino-oxytocin, 1-deamino-1,6-dicarba-oxytocin and derivatives thereof (Kobayashi A., Hase S., Kiyoi R., Sakakibara S.: Bull. Chem. Soc. Japan 42:3491 (1969), Walter R., Yamanaka Y., Sakakibara S., Proc. Nat. Acad. Sci. U.S. 71:1901 (1974). Di-carba oxytocin analogs, however, in which both sulfur atoms have been replaced by methylene groups, although they have prolonged activity, shown such low potencies that very large doses would be required (Barth T., Krejci I., Kupkova B., Jost K., Europ. J. Pharmacol 24:183 (1973); Barth T., Krejci I., Vaneckova J., Jost K: Europ. J. Pharmacol. 25:67 (1974)).
There is also a relatively short-acting oxytocin analog--[2-Tyr(OMe)]-oxytocin, which, in comparision with the natural hormone, has one tenth the contractile activity on the myometrium, but its vasoconstrictor in the same organ is decreased to one hundreth (Hodr J., Stembera Z. K., Brotanek V., Rudinger J., Vondracek J.: The influence of methyl-oxytocin on glycide metabolism of mother and foetus, In "Intra-uterine Dangers to the Foetus", Excerpta Medica, Amsterdam, 1966, p. 445) so that if 10 times as much [2-Tyr(OMe)]-oxytocin as oxytocin itself (w/w) is administered, the same expulsive force from the uterus can be attained without a toxic, hypoxic effect on the fetus or induction of metabolic acidosis in the mother during labor. This short-acting analog is commercially produced and in clinical use (Methyloxytocin SPOFA) and its effectiveness has been demonstrated (Bartschi R., Huter J., Romer V. W., Geburtshilfe u. Frauenheilkunde 32:826 (1972)). Just as with oxytocin, induction of labor with this analog requires a continuous infusion and careful following of uterine contractions and cardiac action of the fetus in order to prevent damage to the latter.
In the sow, as in all other mammals, the biochemical half-life of injected oligopeptide hormones such as oxytocin is only a few minutes and the duration of the myometrial response to single injections is only slightly longer. As in other mammals, the sensitivity of the myometrium in the sow is increased under the influence of estrogen both in vitro and in vivo. While the duration of uterine response can be prolonged by giving large doses of oxytocin, one thereby runs the risk of uterine tetany (particularly during labor) and tachyphylaxis. Ideally the most physiological approach to prolonging oxytocin action until the required clinical task is accomplished would be to administer it by continuous i.v. infusion as in human obstetrics. This is hardly possible under ordinary conditions of veterinary medical practice with large animals. One alternative solution would be a very long-acting analog of oxytocin so that single, or at most two separate, injections could cover several hours of pharmacological activity.